| 1 | PLOS ONE 2007 -1 2：E895 |
|---|---|
| PMID | 17878930 |
| 标题 | DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. |
| Abstract | The role of DNA cytosine methylation, an epigenetic regulator of chromatin structure and function, during normal and pathological brain development and aging remains unclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassing primarily 5' CpG islands of genes related to CNS growth and development, in temporal neocortex of 125 subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric disease cohorts--defined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)--were included. A robust and progressive rise in DNA methylation levels across the lifespan was observed for 8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction with declining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNA methylation levels within the first few months or years after birth. Disease-associated changes were limited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-related change in normal brain. Additionally, methylation studies on sorted nuclei provided evidence for bidirectional methylation events in cortical neurons during the transition from childhood to advanced age, as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the认为T3Ade novo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing in layers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the human cerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portion of genes predominantly by an age-related increase. |
| SCZ关键字 | schizophrenia, schizophrenic |
| 2 | Mol. Pharmacol. 2009 Feb 75: 342-54 |
| PMID | 19029285 |
| 标题 | The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. |
| Abstract | The epigenetic down-regulation of genes is emerging as a possible underlying mechanism of the GABAergic neuron dysfunction inschizophrenia。For example, evidence has been presented to show that the promoters associated with reelin and GAD67 are down-regulated as a consequence of DNA methyltransferase (DNMT)-mediated hypermethylation. Using neuronal progenitor cells to study this regulation, we have previously demonstrated that DNMT inhibitors coordinately increase reelin and GAD67 mRNAs. Here, we report that another group of epigenetic drugs, histone deacetylase (HDAC) inhibitors, activate these two genes with dose and time dependence comparable with that of DNMT inhibitors. In parallel, both groups of drugs decrease DNMT1,认为T3A, and DNMT3B protein levels and reduce DNMT enzyme activity. Furthermore, induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. Our data imply that drug-induced promoter demethylation is relevant for maximal activation of reelin and GAD67 transcription. The results suggest that HDAC and DNMT inhibitors activate reelin and GAD67 expression through similar mechanisms. Both classes of drugs attenuate, directly or indirectly, the enzymatic and transcriptional repressor activities of DNMTs and HDACs. These data provide a mechanistic rationale for the use of epigenetic drugs, individually or in combination, as a potential novel therapeutic strategy to alleviate deficits associated withschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 3 | Eur Neuropsychopharmacol 2012 Aug 22: 596-606 |
| PMID | 22264868 |
| 标题 | Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. |
| Abstract | Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients withschizophrenia。在这项研究中，通过RT-PCR和免疫组织化学染色，我们证明了GNMT在位于大脑皮层，海马，黑质Nigra和小脑的各种神经元中表达。与野生型小鼠相比，GNMT - / - 小鼠在大脑皮层中的肌苷水平明显较低。实时PCR鉴定出参与蛋氨酸代谢的基因（DNMT1和认为T3A), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (Tg-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype ofschizophrenia。GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients withschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 4 | Proc. Natl. Acad. Sci. U.S.A. 2012 Feb 109: 3125-30 |
| PMID | 22315408 |
| 标题 | 微rna - 132在精神分裂症失调implications for both neurodevelopment and adult brain function. |
| Abstract | schizophreniais characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control,schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both theschizophrenicdiscovery cohort and a second, independent set ofschizophrenicsubjects. Analysis of miR-132 target gene expression inschizophreniagene-expression microarrays identified 26 genes up-regulated inschizophreniasubjects. Consistent with NMDA-mediated hypofunction observed inschizophrenic受试者，对成年小鼠的NMDA拮抗剂给药会导致前额叶皮层中的miR-132下调。此外，在青春期期间，miR-132在鼠前额叶皮层中的表达表现出显着的发育调控和重叠与关键的神经发育过程。MIR-132的成年前额叶表达可以通过短暂的后期NMDA受体信号传导的药理抑制来下调。几个关键基因，包括认为T3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adultschizophrenicsubjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present inschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 5 | Proc. Natl. Acad. Sci. U.S.A. 2012 Feb 109: 3125-30 |
| PMID | 22315408 |
| 标题 | 微rna - 132在精神分裂症失调implications for both neurodevelopment and adult brain function. |
| Abstract | schizophreniais characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control,schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both theschizophrenicdiscovery cohort and a second, independent set ofschizophrenicsubjects. Analysis of miR-132 target gene expression inschizophreniagene-expression microarrays identified 26 genes up-regulated inschizophreniasubjects. Consistent with NMDA-mediated hypofunction observed inschizophrenic受试者，对成年小鼠的NMDA拮抗剂给药会导致前额叶皮层中的miR-132下调。此外，在青春期期间，miR-132在鼠前额叶皮层中的表达表现出显着的发育调控和重叠与关键的神经发育过程。MIR-132的成年前额叶表达可以通过短暂的后期NMDA受体信号传导的药理抑制来下调。几个关键基因，包括认为T3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adultschizophrenicsubjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present inschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 6 | PLoS ONE 2014 -1 9: e98182 |
| PMID | 24859147 |
| 标题 | DNA甲基转移酶（DNMT）基因多态性可能是表观遗传易感性精神分裂症的主要事件。 |
| Abstract | DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility toschizophrenia。We screened for polymorphisms in DNA methyltransferases, DNMT1,认为T3A, DNMT3B and DNMT3L in 330schizophreniapatients and 302 healthy controls for association withschizophreniain south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P?=?.004, allele P?=?0.022) and rs2228611 (genotype P?=?0.004, allele P?=?0.022) were found to be significantly associated at genotypic and allelic level withschizophreniain South Indian population. DNMT3B rs2424932 genotype (P?=?0.023) and allele (P?=?0.0063) increased the risk of developingschizophrenia在男性，但不在女性中。DNMT3B RS1569686（基因型P？=？0.027，等位基因P？=？0.033）与早期发作有关schizophreniaand also with family history and early onset (genotype P?=?0.009). DNMT3L rs2070565 (genotype P?=?0.007, allele P?=?0.0026) confers an increased risk of developingschizophreniaat an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation inschizophrenia。 |
| SCZ关键字 | schizophrenia, schizophrenic |
| 7 | Behav. Brain Res. 2016 Mar 300: 123-34 |
| PMID | 26704217 |
| 标题 | Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats. |
| Abstract | schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested thatschizophreniamight have an epigenetic component. We aimed to clarify if epigenetic changes contribute toschizophrenia- 这种菌株的行为。在野生型和DI/DI动物之间比较了行为（遥测，新颖的对象识别，社会识别和社会回避测试的认知，新的对象识别和社会回避测试的认知，社会识别和社会回避测试的认知）和野生型和DI/DI动物之间的表观差异。DNA甲基转移酶1（DNMT1），认为T3A, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmedschizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model ofschizophrenia。它的schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of manyschizophrenia-related substances leading to development ofschizophrenia- 症状。我们的研究证实，没有一个基因，一系列分子的变化是造成大部分的一系列基因的细微变化。schizophreniacases. |
| SCZ关键字 | schizophrenia, schizophrenic |